ORGANIC LETTERS
Catalytic Asymmetric Addition of Aldehydes to Oxocarbenium Ions: A Dual Catalytic System for the Synthesis of Chromenes
2012 Vol. 14, No. 17 4642–4645
Magnus Rueping,* Chandra M. R. Volla, and Iuliana Atodiresei Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, D-52074 Aachen, Germany
[email protected] Received July 27, 2012
ABSTRACT
A synergistic catalytic system for the first asymmetric addition of aldehydes to in situ generated prochiral oxocarbenium ions has been developed. The dual catalytic protocol allows the simultaneous activation of both electrophile and nucleophile and provides access to a variety of valuable chiral 2H-chromenes with excellent enantioselectivities.
Reactions involving in situ generated highly reactive oxocarbenium ions are attracting attention due to their usefulness in the synthesis of complex natural products and bioactive molecules. Whereas Lewis acid mediated diastereoselective addition reactions to oxocarbenium ions are known, catalyzed enantioselective addition reactions to prochiral oxocarbenium ions are less explored.15 The ability to generate oxocarbenium ions and use them in enantioselective catalysis offers numerous (1) The first example of a Lewis acid catalyzed enantioselective allylation of oxocarbenium ions: (a) Braun, M.; Kotter, W. Angew. Chem., Int. Ed. 2004, 43, 514. Lewis acid catalyzed enantioselective addition of metal enolates to oxocarbenium ions, see: (b) Evans, D. A.; Thomson, R. J. J. Am. Chem. Soc. 2005, 127, 10506. For the enantioselective Lewis acid catalyzed addition of β-keto esters to oxocarbenium ions, see: (c) Umebayashi, N.; Hamashima, Y.; Hashizume, D.; Sodeoka, M. Angew. Chem., Int. Ed. 2008, 47, 4196. For the enantioselective Lewis acid catalyzed addition of silyl enol ethers to oxocarbenium ions, see: (d) Kobayashi, S.; Arai, K.; Yamakawa, T.; Chen, Y. J.; Slater, M. M.; Yamashita, Y. Adv. Synth. Catal. 2011, 353, 1927. (2) (a) Reisman, S. E.; Doyle, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2008, 130, 7198. (b) Burns, N. Z.; Witten, M. R.; Jacobsen, E. N. J. Am. Chem. Soc. 2011, 133, 14578. For ketalizations catalyzed by achiral thioureas, see: (c) Kotke, M.; Schreiner, P. R. Tetrahedron 2006, 62, 434. (d) Kotke, M.; Schreiner, P. R. Synthesis 2007, 779. (3) Moquist, P. N.; Kodama, T.; Schaus, S. Angew. Chem., Int. Ed. 2010, 49, 7096. 10.1021/ol302084q r 2012 American Chemical Society Published on Web 08/22/2012
possibilities in the asymmetric synthesis of biologically relevant molecules. These features have been recently successfully explored in the enantioselective synthesis of chromene and isochromane derivatives. In particular, Jacobsen and co-workers designed an elegant chiral anion binding approach for the thiourea catalyzed asymmetric addition of enoxysilanes to chloroisochromans.2a Interesting reports came from the group of Schaus, who developed a catalytic system consisting of a chiral Brønsted acid and an achiral Lewis acid for the addition of boronate esters to oxonium ions derived from chromene acetals.3 More recently, Watson and co-workers reported the asymmetric addition of alkynes to oxocarbenium ions derived (4) (a) Maity, P.; Srinivas, H. D.; Watson, M. P. J. Am. Chem. Soc. 2011, 133, 17142. (b) Watson, M. P.; Maity, P. Synlett 2012, 1705. (5) For the application of chiral Bronsted acids in reactions proceeding c, I.; Vellalath, through oxocarbenium ions intermediates, see: (a) Cori c, I.; M€ S.; List, B. J. Am. Chem. Soc. 2010, 132, 8536. (b) Cori uller, S.; List, B. J. Am. Chem. Soc. 2010, 132, 17370. (c) Terada, M.; Tanka, H.; Sorimachi, K. J. Am. Chem. Soc. 2009, 131, 3430. (d) Zhang, Q.-W.; Fan, C. A.; Zhang, H.-J.; Tu, Y.-Q.; Zhao, Y.-M.; Gu, P.; Chen, Z.-M. c, I.; List, B. Nature 2012, Angew. Chem., Int. Ed. 2009, 48, 8572. (e) Cori 483, 315.
from isochroman acetals by employing chiral copper bisoxazoline complexes.4 Organocatalytic asymmetric additions of aldehydes to various electrophiles, including carbonyl derivatives, imines, activated alkenes and stabilized carbocations,6 have been widely studied in recent years and the field is largely dominated by the use of chiral secondary amines, including proline, prolinol and imidazolidinone derivatives, as catalysts (Scheme 1).7 Despite the recent developments in these two areas of research, the use of oxonium ions as electrophiles in asymmetric enamine catalysis has not been reported yet. This may be due to the intrinsic high reactivity of the oxonium ions which can lead to various undesired side reactions and byproduct formation. Especially, the development of an asymmetric method involving the addition of aldehydes to (iso)chromene or (iso)chromane acetals is of great importance as it would allow the synthesis of (iso)chromene and (iso)chromane derivatives with multiple stereogenic centers. With these considerations in mind our attention has been drawn to 2H-chromenes 3 (2H-1-benzopyrans)8 which constitute a privileged class of structural motifs which is present in many bioactive natural products with antioxidant, antiviral, antifungal and anti-inflammatory activities. Closely related chiral chromans9 include the lipophilic antioxidant vitamine E or rhododaurichromanic acid A which shows potent antiHIV activity. Thus, it is desirable to develop improved procedures for the synthesis of chiral chromenes that could lead to natural products and their analogues with enhanced pharmacological features. 2H-Chromenes 3 might be obtained from chromene acetals which are generally (6) (a) Bergonzini, G.; Vera, S.; Melchiorre, P. Angew. Chem., Int. Ed. 2010, 49, 9685. (b) Shaikh, R. R.; Mazzanti, A.; Petrini, M.; Bartoli, G.; Melchiorre, P. Angew. Chem., Int. Ed. 2008, 47, 8707. (c) Cozzi, P. G.; Benfatti, F.; Zoli, L. Angew. Chem., Int. Ed. 2009, 48, 1313. (d) Gualandi, A.; Emer, E.; Capdevila, M. G.; Cozzi, P. G. Angew. Chem., Int. Ed. 2011, 50, 7842. (7) (a) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471. (b) Melchiorre, P.; Marigo, M.; Carlone, A.; Bartoli, G. Angew. Chem., Int. Ed. 2008, 47, 6138. (c) Barbas, C. F., III Angew. Chem., Int. Ed. 2008, 47, 42. (d) Lelais, G.; MacMillan, D. W. C. Aldrichim. Acta 2006, 39, 79. (8) (a) Nicolaou, K. C.; Pfefferkorn, J. A.; Roecker, A. J.; Cao, G.-Q.; Barluenga, S.; Mitchell, H. J. J. Am. Chem. Soc. 2000, 122, 9939 and the references therein. (b) Chromenes, Chromanones, and Chromones. The Chemistry of Heterocyclic Compounds, Vol. 31; Ellis, G. P., Ed.; Wiley-Interscience: New York, 1977. (9) (a) Chromans and Tocopherols. The Chemistry of Heterocyclic Compounds, Vol. 36; Ellis, G. P., Lockhart, I. M., Eds.; Wiley: New York, 1981. (b) Shen, H. C. Tetrahedron 2009, 65, 3931. (10) (a) Rueping, M.; Koenigs, R. M.; Atodiresei, I. Chem.;Eur. J. 2010, 16, 9350. (b) Allen, A. E.; MacMillan, D. W. C. Chem. Sci. 2012, 3, 633. (11) Selected examples of cooperative chiral secondary amine/ Lewis acid systems in asymmetric synthesis; with CuCl: (a) Allen, E.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, 498. With CuOTf: (b) Yoshida, A.; Ikeda, M.; Hattori, G.; Miyake, Y.; Nishibayashi, Y. Org. Lett. 2011, 13, 592. With InBr3: (c) Motoyama, K.; Ikeda, M.; Miyake, Y.; Nishibayashi, Y. Eur. J. Org. Chem. 2011, 2239. (d) Capdevila, M. G.; Benfatti, F.; Zoli, L.; Stenta, M.; Cozzi, P. G. Chem.;Eur. J. 2010, 16, 11237. With In(OTf)3: (e) Sinisi, R.; Vita, M. V.; Gualandi, A.; Emer, E.; Cozzi, P. G. Chem.;Eur. J. 2011, 17, 7404. With Cu(OTf)2: (f) Montaignac, B.; Praveen, C.; Vitale, M. R.; Michelet, V.; Ratovelomanana-Vidal, V. Chem. Commun. 2012, 48, 6559. with IrCl3: (g) Xiao, J. Org. Lett. 2012, 7, 1716. With Au(I): (h) Chiarucci, M.; di Lillo, M.; Romaniello, A.; Cozzi, P. G.; Cera, G.; Bandini, M. Chem. Sci 2012, 3, 2859. Org. Lett., Vol. 14, No. 17, 2012
stable and easily available on large scale from commercially available starting materials.
Scheme 1. Electrophiles Used in the Enamine Catalysis
We herein demonstrate the first asymmetric addition of aldehydes to catalytically generated oxocarbenium ions. The key to the success of the reaction is to find a compatible set of two different catalysts capable of activating independently both reaction partners, chromene acetals and aldehydes in a synergetic fashion.10,11 Lewis or Brønsted acid catalysis was envisaged for the in situ generation of oxocarbenium ions and the addition of aldehydes was hoped to be achieved with a chiral amine catalyst. However, obstacles including the addition of the amine catalyst to the oxocarbenium ions, the formation of water and resulting side reactions needed to be addressed. The reaction of propionaldehyde 2a with 2-ethoxy-2Hchromene 1a which is available in a two step procedure starting from coumarin, was chosen for the initial studies. The aldehyde product 3a was converted into the corresponding alcohol 4a by reduction with sodium borohydride.12 Initial attempts to apply a chiral amine base/achiral Brønsted acid dual catalytic system were not successful. No product was obtained using either proline A or prolinol B as the chiral base catalyst in combination with various Brønsted acids catalysts13a including carbonic, sulfonic or phosporic acids. Traces of the desired product were observed with the imidazolidinone salt C as catalyst.14 Hence our attention turned to a Lewis base/Lewis acid dual catalytic system. After extensive examinations we were delighted to find that use of catalytic amounts of Yb(OTf)313b and TFA imidazolidinone salt C gave a clean reaction in DCM at room temperature, affording the product 4a in 94% yield and moderate enantiomeric excess (Table 1, entry 3). Gratifyingly, we found that using the free amine D instead of the corresponding trifluoroacetate salt has a tremendous effect on the selectivity of the reaction. Using catalytic amounts of Yb(OTf)3 in combination with the free amine D led to the desired product in 84% yield and 89:11 er (Table 1, entry 6). A higher enantioselectivity (er = 98:2) was observed when the reaction was performed at 0 °C (Table 1, entry 9). (12) The stable alcohol products allowed the easier analysis. (13) (a) Proline A and prolinol B were tested in combination with benzoic acid, p-nitro benzoic acid, p-toluenesulfonic acid and diphenyl phosphoric acid as catalysts. (b) The use of scandium and indium triflate resulted in lower yields. For Yb(OTf)3 in enamine catalysis: Mase, N.; Tanaka, F.; Barbas, C. F, III Org. Lett. 2003, 5, 4369. (14) (a) Jen, W. S.; Wiener, J. J. M.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122, 9874. (b) Paras, N. A.; MacMillan, D. W. C. J. Am. Chem. Soc. 2001, 123, 4370. 4643
Other secondary amines such as FH gave similar results except for the trans catalyst E, which gave the product in only 7% ee. Evaluation of different solvents led to the conclusion that chlorinated solvents are better in terms of yield. Although the selectivity was slightly better (er = 98.5:1.5) by further lowering the temperature to 10 °C, the reaction became very slow (Table 1, entry 16).
Table 1. Optimization of the Aldehyde Addition to Oxocarbenium Ions
entry cat. solvent temp (°C) time (h) 1 2 3 4c 5 6 7 8 9 10 11 12 13d 14d 15e 16
A B C C D E C D F G H D D D D
CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CHCl3 Toluene CH2Cl2 CH2Cl2
rt rt rt rt rt rt rt 0 0 0 0 0 0 0 0 10
24 24 3 24 24 24 2 24 48 48 48 48 48 48 72 72
dr
yielda (%)
erb
50:50
94 traces
76:24
52:48 50:50 52:48 68:32 51:49 68:32 68:32 52:48 50:50
85 67 89 84 78 76 74 58 27 traces 35
89:11 53.5:46.5 80:20 98:2 94.5:5.5 98:2 97.5:2.5 95.5:4.5 97.5:2.5
68:32
98.5:1.5
a Yield for the two diastereomers after column chromatography. Enantiomeric ratios were determined by HPLC analysis. c Reaction without Yb(OTf)3. d Reaction was not complete. e 4 A˚ MS was added to the reaction. b
With the optimized conditions in hand, we explored the substrate scope of this transformation by employing differently substituted chromene acetals and aldehydes (Table 2). Use of methyl acetal instead of the ethyl acetal gave similar results (Table 2, entry 2 vs 1). Furthermore, when the reaction was conducted on 0.5 g scale, the product was isolated in 78% yield with a good enantiomeric excess of 95:5 er (Table 2, entry 3). In addition to propanal, various other aldehydes were tested in the reaction (Table 2, entries 49). Less reactive aldehydes reacted sluggishly with the chromene acetal at 0 °C. Pleasingly, we found that slightly increasing the temperature to 5 °C allows a clean reaction with the acetal. 4644
Table 2. Scope of the Reaction Using Different Chromene Acetals and Aldehydes
entrya
R
R0
4
dr
yieldb (%)
erc
1 2d 3e 4 5 6 7 8 9 10 11 12 13 14 15
H H H H H H H H H 6-Br 6-Me 6-Me 7-Me 7-Me 7-MeO
Me Me Me Et n-Pr n-Bu Bn 8-nonenyl OBn Me Me n-Pr Me Et Me
4a 4a 4a 4b 4c 4d 4e 4f 4g 4h 4i 4j 4k 4l 4m
68:32 68:32 67:33 66:34 73:27 68:32 64:36 65:35 59:41 67:33 64:36 69:31 68:32 74:26 64:36
84 82 78 82 69 76 72 72 89 78 84 73 81 78 74
98:2 98.5:1.5 95:5 97.5:2.5 94.5:5.5 94.5:5.5 93.5:6.5 92.5:7.5 86:14 98:2 97:3 87.5:12.5 97:3 90:10 97.5:2.5
a Addition reactions were performed at 5 °C and in the case of propanal (R0 = Me) at 0 °C for 48 h. b Yield for the two diastereomers after column chromatography. c Enantiomeric ratios were determined by HPLC analysis. d Methyl chromene acetal was used in the reaction. e Reaction was performed on a larger scale (0.5 g 1a).
In general the scope of this transformation was found to be relatively wide as different substituents on the chromenes led to products in good yields and excellent enantioselectivities (Table 2, entries 1015). The bromine substituted coumarin derivative (Table 2, entry 10) is particularly interesting as the product can be further functionalized by transition metal-catalyzed carbon carbon cross-coupling reactions, alkoxylations, or aminations. The synthetic utility of the addition products was illustrated by converting the carbonyl group into other useful functionalities (Scheme 2). As described above, aldehyde 3a can easily be reduced by sodium borohydride to afford the appropriate alcohol 4a (Scheme 2, top). Enal esters are useful building blocks in organic synthesis because of their excellent electrophilic character. Treatment of aldehyde 3a with 1.2 equivalents of commercially available phosphorane in DCM gave the product 5a in 92% yield after 2 h (Scheme 2, middle). Aliphatic carboxylic acids can also be prepared by employing sodium chlorite as the stoichiometric oxidant (Scheme 2, bottom). By a combination of theoretical studies and CD- and NMR-spectroscopy, the absolute configuration of the two diastereomeric alcohol products 4a has been determined to be as S,R and S,S for the major and minor diastereomers, respectively.15,16 A model explaining the stereoselective addition of aldehydes to the oxonium ions is depicted in Scheme 3. (15) See Supporting Information for further details. (16) Rueping, M.; Uria, U.; Lin, M.-Y.; Atodiresei, I. J. Am. Chem. Soc. 2011, 133, 3732. Org. Lett., Vol. 14, No. 17, 2012
Scheme 2. Functionalization of the Addition Products
The aldehyde reacts with the imidazolidinone catalyst to form enamine 7, which possesses the stable E-configured carboncarbon double bond facing away from the geminal dimethyl groups.1719 The bulky benzyl group present on the top face controls the addition of the enamine to the oxonium ion. The benzyl group of the catalyst shields the Re face of the enamine and subsequently the oxonium ion will be attacked from the enamine Si face,20 leading to the (R)-configuration at the center bearing the aldehyde for both diastereomers. The configuration at the second chiral center of the two diastereomeric products is given by the attack on either Si or Re face of the planar oxonium ion and has been established by comparing the measured and theoretically calculated CD-spectra for the corresponding alcohols 4a with spectra of known members from the same class of compounds.15,16 In summary, we have developed the first asymmetric addition of aldehydes to prochiral oxocarbenium ions yielding valuable chiral 2H-chromene derivatives. Given the difficulties that typically arise from the in situ formation of highly reactive oxocarbenium ions and the side (17) For a NMR study on the conformation of enamines derived from imidazolidinone D in solution: Peelen, T. J.; Chi, Y.; Gellman, S. H. J. Am. Chem. Soc. 2005, 127, 11598. (18) For the use of imidazolidinone D as chiral auxiliary, see: (a) Solodin, I.; Goldberg, Y.; Zelcans, G.; Lukevics, E. J. Chem. Soc., Chem. Commun. 1990, 1321. (b) Solodin, I. Monatsh. Chem. 1992, 123, 565. For selected structural and spectroscopic studies on the iminium ions derived from imidazolidinone D, see: (c) Brazier, J. B.; Evans, G.; Gibbs, T. J. K.; Coles, S. J.; Hursthouse, M. B.; Platts, J. A.; Tomkinson, N. C. O. Org. Lett. 2009, 11, 133. (d) Groselj, U.; Schweizer, W. B.; Ebert, M.-O.; Seebach, D. Helv. Chim. Acta 2009, 92, 1. (e) Seebach, D.; Groselj, U.; Schweizer, W. B.; Grimme, S.; M€ uck-Lichtenfeld, C. Helv. Chim. Acta 2010, 93, 1. (f) Um, J. M.; Gutierrez, O.; Schoenebeck, F.; Houk, K. N.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, 6001. Recent review on quantum mechanical investigations: (g) Cheong, P. H.€ -u €m, N.; Houk, K. N. Chem. Y.; Legault, C. Y.; Um, J. M.; C-elebi-Olc Rev. 2011, 111, 5042. (19) For an important study on imidazolidionone-derived enamines and their addition to carbenium ions, see: Lakhdar, S.; Maji, B.; Mayr, H. Angew. Chem., Int. Ed. 2012, 51, 5739. (20) Mangion, I. K.; Northrup, A. B.; MacMillan, D. W. C. Angew. Chem., Int. Ed. 2004, 43, 6722.
Org. Lett., Vol. 14, No. 17, 2012
Scheme 3. Stereochemical Model for the Addition of Propanal to the Oxonium Ion
reactions that can occur, the results presented here are very encouraging. A catalytic system consisting of an achiral Lewis acid and a chiral imidazolidinone catalyst which simultaneously activates the electrophile and nucleophile, was key to afford the products with excellent enantioselectivities. The resulting optically active aldehydes can be subjected to different functional group transformations to form the corresponding alcohols, enal esters and acids. The stereochemical outcome of this combined metal and organocatalyzed reaction provides the basis for further extensions. Together with previously reported amine catalyzed additions of aldehydes to imines, carbonyl groups, and carbocations, the addition to oxocarbenium ions presented here not only expands the repertoire of Lewis base catalysis but also provides fast and ready access to valuable chromenes and chromans in a highly enantioselective fashion. It is anticipated that this new mode of activation will find application in related reactions of oxocarbenium ions and is the focus of ongoing research. Acknowledgment. Financial support was provided by the European Research Council. C.M.R.V. gratefully acknowledges the Alexander von Humboldt Foundation (AvH) for a postdoctoral fellowship. Supporting Information Available. This material is available free of charge via the Internet at http://pubs.acs.org. The authors declare no competing financial interest.
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